GENETIC

DISORDERS
 DISEASES
•GENETIC
•ENVIRONMENTAL
•BOTH
 MUTATIONS
• PERMANENT change in DNA

–GENOME MUTATION: (whole

chromosome)
–CHROMOSOME MUTATION: (visible
chromosome change)
–GENE MUTATION: (may, and often, result
in a single base error)
 GENE MUTATION
• DELETION OF A SINGLE BASE
• SUBSTITUTION OF A SINGLE BASE
POINT MUTATION
 GENE MUTATION
• POINT MUTATION within a coding sequence:
VAL-GLU
• MUTATIONS in NON-coding sequences
defective transcription, regulation
• DELETIONS/INSERTIONS frameshift
mutation, involvement is NOT a multiple of 3
• Tri-nucleotide REPEATS, e.g., CGG repeats
many times in fragile X syndrome
 GENE MUTATIONS
• INTERFERE with protein synthesis
• SUPPRESS transcription, DNARNA
• PRODUCE abnormal mRNA
• DEFECTS carried over into TRANSLATION
• ABNORMAL proteins WITHOUT
impairing syntheses
 GENETIC DISORDERS
• SINGLE gene mutations, following
classical MENDELIAN inheritance
patterns the most
• MULTIFACTORIAL inheritance
• CHROMOSOMAL disorders
MENDELIAN inheritance patterns
• AUTOSOMAL DOMINANT
• AUTOSOMAL RECESSIVE
• SEX-LINKED (recessive), involving
“X” chromosome
 AUTOSOMAL DOMINANT
• Disease is in HETEROZYGOTES
• NEITHER parent may have the disease (NEW mut.)
• REDUCED PENETRANCE (environment?,
other genes?)
• VARIABLE EXPRESSIVITY (environment?,
other genes?)
• May have a DELAYED ONSET
• Usually result in a REDUCED PRODUCTION
or INACTIVE protein
 AUTOSOMAL DOMINANT
• HUNTINGTON DISEASE
• NEUROFIBROMATOSIS
• MYOTONIC DYSTROPHY
• TUBEROUS SCLEROSIS
• POLYCYSTIC KIDNEY
• HEREDITARY SPHEROCYTOSIS
• VON WILLEBRAND DISEASE
• MARFAN SYNDROME
• EHLERS-DANLOS SYNDROMES (some)
• OSTEOGENESIS IMPERFECTA
• ACHONDROPLASIA
• FAMILIAL HYPERCHOLESTEROLEMIA
• ACUTE INTERMITTENT PORPHYRIA
AUTOSOMAL DOMINANT PEDIGREE

1) BOTH SEXES INVOLVED

2) GENERATIONS NOT SKIPPED

 AUTOSOMAL RECESSIVE
• Disease is in HOMOZYGOTES
• More UNIFORM expression than AD
• Often COMPLETE PENETRANCE
• Onset usually EARLY in life
• NEW mutations rarely detected clinically
• Proteins show LOSS of FUNCTION
• Include ALL inborn errors of metabolism
• MUCH more common that autosomal dominant
 AUTOSOMAL RECESSIVE
• CF Hgb S
• PKU THALASSEMIAS
• GALACTOSEMIA CONG. ADRENAL HYPERPLASIA
• HOMOCYSTINURIA EHLERS-DANLOS (some)
• LYSOSOMAL STORAGE ALKAPTONURIA
• Α-1 ANTITRYPSIN NEUROGENIC MUSC. ATROPHIES
• WILSON DISEASE FRIEDREICH ATAXIA
• HEMOCHROMATOSIS SPINAL MUSCULAR ATROPHY
• GLYCOGEN STORAGE
DISEASES
AUTOSOMAL RECESSIVE PEDIGREE

1) BOTH SEXES
INVOLVED
2) GENERATIONS
SKIPPED
 SEX (“X”) LINKED
• MALES ONLY
• HIS SONS are OK, right?
• ALL his DAUGHTERS are CARRIERS
• The “Y” chromosome is NOT homologous to
the “X”, i.e., the concept of
dominant/recessive has no meaning here
• HETEROZYGOUS FEMALES have no
phenotypic expression (carriers)….usually,
this means autosomal “recessive”, right?
 SEX (“X”) LINKED
• DUCHENNE MUSCULAR DYSTROPHY
• HEMOPHILIA , A and B
• G6PD DEFICIENCY
• AGAMMAGLOBULINEMIA
• WISKOTT-ALDRICH SYNDROME
• DIABETES INSIPIDUS
• LESCH-NYHAN SYNDROME
• FRAGILE-X SYNDROME
 SEX LINKED PEDIGREE

1) MALES ONLY, sons of affected males are OK

2) GENERATION SKIPPING DOESN’T MATTER
 SINGLE GENE DISORDERS
• ENZYME DEFECT (Most of them, e.g., PKU)
– Accumulation of substrate
– Lack of product
– Failure to inactivate a protein which causes damage
• RECEPTOR/TRANSPORT PROTEIN DEFECT (Familial
Hypercholesterolemia)
• STRUCTURAL PROTEIN DEFECT (Marfan, Ehl-Dan)
– Structure
– Function
– Quantity
• ENZYME DEFECT WHICH INCREASES DRUG
SUSCEPTIBILITY: G6PDPrimaquine
 STRUCTURAL PROTEIN DEFECTS
• Marfan Syndrome
– Fibrillin-1 defect (not -2 or -3)
– Tall, dislocated lens, aortic arch aneurysms, etc.
– Abraham Lincoln?, Osama bin-Laden

• Ehlers-Danlos Syndromes (AD, AR)

– Multiple (6?) different types
– Classical, Hypermob., Vasc., KyphoSc., ArthChal., Derm
– Various collagen defects
– Hyperelastic skin, hyperextensible joints
 RECEPTOR PROTEIN DEFECTS
• FAMILIAL HYPERCHOLESTEROLEMIA
– LDL RECEPTOR defect
– Cholesterol TRANSPORT across liver cell impaired
– ergo, CHOLESTEROL BUILDUP IN BLOOD
• “Scavenger System” for CHOL kicks in, i.e.,
MACROPHAGES
• YOU NOW KNOW THE REST OF THE STORY
• YOU NOW KNOW WHY MACROPHAGES are
“FOAMY”
 ENZYME DEFICIENCIES
• BY FAR, THE LARGEST KNOWN
CATEGORY
– SUBSTRATE BUILDUP
– PRODUCT LACK
– SUBSTRATE could be HARMFUL
• LYSOSOMAL STORAGE DISEASES
comprise MOST of them
 LYSOSOMAL STORAGE DISEASES
• GLYCOGEN STORAGE DISEASES
• SPHINGOLIPIDOSES (Gangliosides)
• SULFATIDOSES
• MUCOPOLYSACCHARIDOSES
• MUCOLIPIDOSES
• OTHER
– Fucosidosis, Mannosidosis, Aspartylglycosaminuria
– WOLMAN, Acid phosphate deficiency
GLYCOGEN STORAGE DISEASES
• MANY TYPES (at least 10)
• Type 2 (Pompe), von Gierke, McArdle, most
studied and discussed, and referred to
• Storage sites: Liver, Muscle, Heart
 SPHINGOLIPIDOSES
• MANY types, Tay-Sachs most often referred to
– GANGLIOSIDES are ACCUMULATED, due to a
hexoseaminidase A deficiency
– Ashkenazi Jews (1/30 are carriers)
– CNS neurons a site of accumulation
– CHERRY RED spot in Macula
 SULFATIDOSES
• MANY types, but the metachromatic
leukodystrophies (CNS), Krabbe, Fabry,
Gaucher, and Niemann-Pick (A and B) are
most commonly referred to
• SULFATIDES, CEREBROSIDES,
SPHINGOMYELIN are the accumulations
 NIEMANN-PICK
• TYPES A, B, C
• SPHINGOMYELIN BUILDUP
• MASSIVE SPLENOMEGALY
• ALSO in ASHKANAZI JEWS
• OFTEN FATAL in EARLY LIFE, CNS, ORGANOMEGALY
 GAUCHER DISEASE
• GLUCOCEREBROSIDE BUILDUP, due to
glucocerebrocidase deficiency
• 99% are type I, NO CNS involvement
• ALL MACROPHAGES, liv, spl, nodes, marrow
 MUCOPOLYSACCHARIDOSES

• HURLER/HUNTER, for I and II, respectively

• DERMATAN sulfate, HEPARAN sulfate
buildup, respectively
– coarse facial features
– clouding of the cornea
– joint stiffness
– mental retardation
– URINARY EXCRETION of SULFATES COMMON
 OTHER LYSOSOMAL STORAGE DIS.
• FUCOSIDOSIS
• MANNOSIDOSIS
• ASPARTYLGLYCOSAMINURIA
• WOLMAN (CHOL., TRIGLYCERIDES)
• ACID PHOSPHATASE DEFICIENCY (PHOS. ESTERS)
 ALCAPTONURIA
• NOT a LYSOSOMAL ENZYME DISEASE
• FIRST ONE TO BE DESCRIBED
• HOMOGENTISIC ACID
• HOMOGENTISIC ACID OXIDASE
–BLACK URINE
–BLACK NAILS (OCHRONOSIS), SKIN
–BLACK JOINT CARTILAGE (SEVERE ARTHRITIS)
 NEUROFIBROMATOSIS
• 1 and 2
• 1-von Recklinghausen
• 2- “acoustic” neurofibromatosis

• 1
– Neurofibromas, café-au-lait, Lisch nodules
 NEUROFIBROMATOSIS
• 1 and 2
• 1-von Recklinghausen
• 2- “acoustic” neurofibromatosis

• 2
– Bilateral acoustic neuromas and multiple meningiomas
 MULTIFACTORIAL INHERITANCE

• Multi-”FACTORIAL”, not just multi-GENIC

• “SOIL” theory
• Common phenotypic expressions governed by
“multifactorial” inheritance
– Hair color
– Eye color
– Skin color
– Height
– Intelligence
– Diabetes, type II
 FEATURES of
multifactorial inheritance
• Expression determined by NUMBER of genes
• Overall 5% chance of 1st degree relatives having it
• Identical twins >>>5%, but WAY less than 100%
• This 5% is increased if more children have it
• Expression of CONTINUOUS traits (e.g.,
height) vs. DISCONTINUOUS traits (e.g., Diabetes I)
“MULTIFACTORIAL” DISORDERS
• Cleft lip, palate
• Congenital heart disease
• Coronary heart disease
• Hypertension
• Gout
• Diabetes
• Pyloric stenosis
• MANY, MANY, MANY MORE, perhaps MOST!
 KARYOTYPING
• Defined as the study of CHROMOSOMES
• 46 = (22x2) + X + Y
• Conventional notation is “46,XY” or “46,XX”
• G(iemsa)-banding, 500 bands per haploid
recognizable
• Short (“p”-etit) arm = p, other (long) arm = q
 More KARYOTYPING info
• A,B,C,D,E,F,G depends on chromosome length
– A longest
– G shortest
• Groups within these letters depend on the p/q
ratio
• ARMREGIONBANDSub-BAND,
numbering from the centromere progressing
distad
 F.I.S.H. (gene “probes”)

greatly enhances G-banding

• Fluorescent In-
Situ
Hybridization
• Uses fluorescent
labelled DNA
fragments, ~10,000
base pairs, to bind (or
not bind) to its
complement
 FISH
• SUBTLE MICRODELETIONS
• COMPLEX TRANSLOCATIONS
• AND TELOMERE ALTERATIONS
TRIPLE CHROMOSOME #20 A DELETION in
CHROMOSOME #22
SPECTRAL KARYOTYPING
 CYTOGENETIC DISORDERS
• DEFINITIONS:
– EUPLOID
–ANEUPLOID (NOT AN EXACT MULTIPLE OF 23)
– MONOSOMY, AUTOSOME OR SEX
– TRISOMY, AUTOSOME OR SEX
– DELETION
– BREAKAGE
MORE DEFINITIONS
COMMON CYTOGENETIC DISEASES
• AUTOSOMES
– TRISOMY-21 (DOWN SYNDROME)
– 8, 9, 13 (Patau), 18 (Edwards), 22
– 22q.11.2 deletion
• SEX CHROMOSOMES
–KLINEFELTER: XXY, XXXY, etc.
–TURNER: XO
TRISOMY-21
 TRISOMY-21
• Most trisomies (monosomies, aneuploidy) are
from maternal non-disjunction
• (non-disjunction or anaphase lag are BOTH
possible)
• #1 cause of mental retardation
• Maternal age related
• Congenital Heart Defects, risk for acute leukemias,
GI atresias
• Most LOVABLE of all God’s children? Why?
 Chromosome 22q11.2
Deletion Syndrome
• Because of a DELETION, this cannot be detected
by standard karyotyping and needs FISH
• Cardiac defects, DiGeorge syndrome,
velocardiofacial, CATCH* (Learn the mnemonic)
SEX CHROMOSOME DISORDERS
• Problems related to sexual development and
fertility
• Discovered at time of puberty
• Retardation related to the number of X
chromosomes
• If you have at least ONE “Y” chromosome,
you are male
 KLINEFELTER (XXY, XXXY, etc.)

• Hypogonadism found at puberty

• #1 cause of male infertility
• NO retardation unless more X’s
• 47, XXY 82% of the time
• L----O----N----G legs, atrophic testes,
small penis
 TURNER (XO)
• 45, X is the “proper” designation
• Mosaics common
• Often, the WHOLE chromosome is not
missing, but just part
• NECK “WEBBING”, “STREAK “ OVARIES
• EDEMA of HAND DORSUM
• CONGENITAL HEART DEFECTS most FEARED
 HERMAPHRODITES
• GENETIC SEX is determined by the PRESENCE or ABSENCE
of a “Y” chromosome, but there is also, GONADAL
(phenotypic), and DUCTAL sex
• TRUE HERMAPHRODITE: OVARIES AND TESTES, often on
opposite sides (VERY RARE)

• PSEUDO-HERMAPHRODITE:
– MALE: TESTES with female characteristics (XY)
– FEMALE: OVARIES with male characteristics (XX)
 SINGLE GENE, NON-Mendelian
• Triplet repeats
–Fragile X (CGG)
–Others: ataxias, myotonic dystrophy
• Mitochondrial Mutations: (maternal)
(LEBER HEREDITARY OPTIC NEUROPATHY)
• Genomic “IMPRINTING”: (Inactivation of
maternal or paternal allele, contradicts Mendel)
• Gonadal “MOSAICISM”: (only gametes have
mutated cells)
 MOLECULAR DX by DNA PROBES

• BIRTH DEFECTS, PRE- or POST- NATAL

• TUMOR CELLS
• CLASSIFICATIONS of TUMORS
• IDENTIFICATION of PATHOGENS
• DONOR COMPATIBILITY
• PATERNITY
• FORENSIC
• TUMOR DNA in BLOOD
 H&E tissue
structures

Immuno-
Antigen
Proteins (IHC)

GENES that
MAKE those
PROTEINS